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  • 1
    In: GeroScience, Springer Science and Business Media LLC, Vol. 44, No. 3 ( 2022-06), p. 1807-1823
    Abstract: The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.
    Type of Medium: Online Resource
    ISSN: 2509-2715 , 2509-2723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2886418-9
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  • 2
    In: Journal of Alzheimer's Disease Reports, IOS Press, Vol. 5, No. 1 ( 2021-06-03), p. 443-468
    Abstract: Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.
    Type of Medium: Online Resource
    ISSN: 2542-4823
    Language: Unknown
    Publisher: IOS Press
    Publication Date: 2021
    detail.hit.zdb_id: 2955863-3
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  • 3
    In: Experimental Physiology, Wiley, Vol. 108, No. 1 ( 2023-01), p. 135-145
    Abstract: What is the central question of this study? How does the microvascular perfusion of striated muscle change during the dynamic developmental period between the late gestation fetus and early neonate? What is the main finding and its importance? In both myocardium and skeletal muscle, perfusion of striated muscle is significantly reduced in the neonate compared to the late term fetus, but flow reserve is unchanged. The results suggest striated muscle capillary networks grow more slowly relative to the myofibres they nourish during the perinatal period. Abstract Microvascular perfusion of striated muscle is an important determinant of health throughout life. Birth is a transition with profound effects on the growth and function of striated muscle, but the regulation of microvascular perfusion around this transition is poorly understood. We used contrast‐enhanced ultrasound perfusion imaging (CEUS) to study the perfusion of left ventricular myocardium and hindlimb biceps femoris, which are populations of muscle with different degrees of change in pre‐ to postnatal workloads and different capacities for postnatal proliferative growth. We studied separate groups of lambs in late gestation (135 days’ gestational age; 92% of term) and shortly after birth (5 days’ postnatal age). We used CEUS to quantify baseline perfusion, perfusion during hyperaemia induced by adenosine infusion (myocardium) or electrically stimulated unloaded exercise (skeletal muscle), flow reserve and oxygen delivery. We found heart‐to‐body weight ratio was greater in neonates than fetuses. Microvascular volume and overall perfusion were lower in neonates than fetuses in both muscle groups at baseline and with hyperaemia. Flux rate differed with muscle group, with myocardial flux being faster in neonates than fetuses, but skeletal muscle flux being slower. Oxygen delivery to skeletal muscle at baseline was lower in neonates than fetuses, but was not significantly different in myocardium. Flow reserve was not different between ages. Given the significant somatic growth, and the transition from hyperplastic to hypertrophic myocyte growth occurring in the perinatal period, we postulate that the primary driver of lower neonatal striated muscle perfusion is faster growth of myofibres than their associated capillary networks.
    Type of Medium: Online Resource
    ISSN: 0958-0670 , 1469-445X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1493802-9
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  • 4
    Online Resource
    Online Resource
    Japanese Society of Animal Reproduction ; 2005
    In:  Journal of Reproduction and Development Vol. 51, No. 1 ( 2005), p. 59-68
    In: Journal of Reproduction and Development, Japanese Society of Animal Reproduction, Vol. 51, No. 1 ( 2005), p. 59-68
    Type of Medium: Online Resource
    ISSN: 0916-8818 , 1348-4400
    Language: English
    Publisher: Japanese Society of Animal Reproduction
    Publication Date: 2005
    detail.hit.zdb_id: 2039060-9
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  • 5
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2001
    In:  Pediatric Research Vol. 50, No. 5 ( 2001-11), p. 641-649
    In: Pediatric Research, Springer Science and Business Media LLC, Vol. 50, No. 5 ( 2001-11), p. 641-649
    Type of Medium: Online Resource
    ISSN: 0031-3998 , 1530-0447
    Language: Unknown
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2001
    detail.hit.zdb_id: 2031217-9
    SSG: 12
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  • 6
    In: Experimental Physiology, Wiley, Vol. 95, No. 1 ( 2010-01-01), p. 131-139
    Type of Medium: Online Resource
    ISSN: 0958-0670
    Language: English
    Publisher: Wiley
    Publication Date: 2010
    detail.hit.zdb_id: 1493802-9
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  • 7
    Online Resource
    Online Resource
    American Physiological Society ; 2023
    In:  Physiology Vol. 38, No. S1 ( 2023-05)
    In: Physiology, American Physiological Society, Vol. 38, No. S1 ( 2023-05)
    Abstract: Introduction: The myocardium is made up of many elements that each play an important role in heart function. The contractile cardiomyocytes proliferate prenatally, and become terminally differentiated in the weeks leading up to birth. Despite a loss of ~ 1/3 of the cardiomyocytes about 1 week before birth, the hearts continue to increase in size (Jonker et al., 2015). At birth, the demands on the cardiovascular system change, which may affect the relative cellular makeup of the myocardium. In this study, we determined the fractional composition of the myocardium in four different ages around the time of birth. Methods: Hearts, arrested in diastole, were collected from control fetal (135d and 142d gestational age; dGA; term is 147d) and newborn (1d and 5d postnatal age; PN) lambs. Sections of left ventricle were fixed (4% paraformaldehyde), paraffin embedded and stained (Masson’s Trichrome). Images (400x) were analyzed by unbiased sampling (grid system, FIJI) to classify according to these categories: cardiomyocyte cell body, cardiomyocyte nucleus, blood vessel lumen, blood vessel wall, collagen, non-collagen connective tissue. All values are represented as percent of total area (±SD). Groups (n=3-4 each age) were compared by 1-way ANOVA followed, if indicated, by Tukey's multiple comparisons test. Males and females were both represented in each age (135dGA, 143dGA, 1dPN, 5dPN: n=1/2, 2/2, 3/1, 2/1, respectively). Results: The average area composed of cardiomyocyte for all groups was 81.7 ± 7.4%, and did not differ between ages. The average area composed of vasculature for all groups was 8.6 ± 5.2%, and did not change with age. Connective tissue area was 3-fold greater at 1dPN (8.5 ± 3.6%) than 143dGA (2.8 ± 1.2%, P 〈 0.05) and 5dPN (2.5 ± 0.8%, P 〈 0.05). This was not due to more collagen, which did not differ between ages. Further analysis of the cardiomyocyte fraction indicated that the nucleus was 60% larger (compared to total myocyte area) at 1dPN (P 〈 0.04; in advancing age order: 18.2 ± 3.3%, 14.2 ± 1.0%, 26.3 ± 4.9%, 17.1 ± 1.8%). Conclusion: Our preliminary analysis indicates little change in the cellular composition of the left ventricle myocardium, save for a transient increase in connective tissue area and larger nuclei per cardiomyocyte area 1 day after birth. A change in glycogen after birth could be a factor that leads to increased cardiomyocyte nuclear area per cytoplasm and increased relative fraction of connective tissue. This study was funded by NIH NHLBI R01HL142483. KAVR was funded by a NIH supplement to R01HL142483. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
    Type of Medium: Online Resource
    ISSN: 1548-9213 , 1548-9221
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 3115360-4
    detail.hit.zdb_id: 2005759-3
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Wiley ; 2022
    In:  The Journal of Physiology Vol. 600, No. 3 ( 2022-02), p. 655-670
    In: The Journal of Physiology, Wiley, Vol. 600, No. 3 ( 2022-02), p. 655-670
    Abstract: At birth, the mammalian myocardium switches from using carbohydrates as the primary energy substrate to free fatty acids as the primary fuel. Thus, a compromised switch could jeopardize normal heart function in the neonate. Placental embolization in sheep is a reliable model of intrauterine growth restriction (IUGR). It leads to suppression of both proliferation and terminal differentiation of cardiomyocytes. We hypothesized that the expression of genes regulating cardiac fatty acid metabolism would be similarly suppressed in IUGR, leading to compromised processing of lipids. Following 10 days of umbilicoplacental embolization in fetal sheep, IUGR fetuses had elevated circulating long‐chain fatty acylcarnitines compared with controls (C14: CTRL 0.012 ± 0.005 nmol/ml vs . IUGR 0.018 ± 0.005 nmol/ml, P 〈 0.05; C18: CTRL 0.027 ± 0.009 nmol/mol vs . IUGR 0.043 ± 0.024 nmol/mol, P 〈 0.05, n = 12 control, n = 12 IUGR) indicative of impaired fatty acid metabolism. Uptake studies using fluorescently tagged BODIPY‐C12‐saturated free fatty acid in live, isolated cardiomyocytes showed lipid droplet area and number were not different between control and IUGR cells. mRNA levels of sarcolemmal fatty acid transporters (CD36, FATP6), acylation enzymes (ACSL1, ACSL3), mitochondrial transporter (CPT1), β‐oxidation enzymes (LCAD, HADH, ACAT1), tricarboxylic acid cycle enzyme (IDH), esterification enzymes (PAP, DGAT) and regulator of the lipid droplet formation (BSCL2) gene were all suppressed in IUGR myocardium ( P 〈 0.05). However, protein levels for these regulatory genes were not different between groups. This discordance between mRNA and protein levels in the stressed myocardium suggests an adaptive protection of key myocardial enzymes under conditions of placental insufficiency. image Key points The fetal heart relies on carbohydrates in utero and must be prepared to metabolize fatty acids after birth but the effects of compromised fetal growth on the maturation of this metabolic system are unknown. Plasma fatty acylcarnitines are elevated in intrauterine growth‐restricted (IUGR) fetuses compared with control fetuses, indicative of impaired fatty acid metabolism in fetal organs. Fatty acid uptake and storage are not different in IUGR cardiomyocytes compared with controls. mRNA levels of genes regulating fatty acid transporter and metabolic enzymes are suppressed in the IUGR myocardium compared with controls, while protein levels remain unchanged. Mismatches in gene and protein expression, and increased circulating fatty acylcarnitines may have long‐term implications for offspring heart metabolism and adult health in IUGR individuals. This requires further investigation.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1475290-6
    SSG: 12
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  • 9
    In: The Journal of Physiology, Wiley, Vol. 580, No. 2 ( 2007-04-15), p. 639-648
    Type of Medium: Online Resource
    ISSN: 0022-3751
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2007
    detail.hit.zdb_id: 1475290-6
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    Wiley ; 2019
    In:  The Journal of Physiology Vol. 597, No. 8 ( 2019-04), p. 2163-2176
    In: The Journal of Physiology, Wiley, Vol. 597, No. 8 ( 2019-04), p. 2163-2176
    Abstract: Plasma thyroid hormone (tri‐iodo‐ l ‐thyronine; T 3 ) concentrations rise near the end of gestation and is known to inhibit proliferation and stimulate maturation of cardiomyocytes before birth. Thyroid hormone receptors are required for the action of thyroid hormone in fetal cardiomyocytes. Loss of thyroid hormone receptor (TR)α1 abolishes T 3 signalling via extracellular signal‐related kinase and Akt in fetal cardiomyocytes. The expression of TRα1 and TRβ1 in ovine fetal myocardium increases with age, although TRα1 levels always remain higher than those of TRβ1. Near term fetal cardiac myocytes are more sensitive than younger myocytes to thyroid receptor blockade by antagonist, NH3, and to the effects of TRα1/α2 short interfering RNA. Although T 3 is known to abrogate ovine cardiomyocyte proliferation stimulated by insulin‐like growth factor 1, this effect is mediated via the genomic action of thyroid hormone receptors, with little evidence for non‐genomic mechanisms.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 1475290-6
    SSG: 12
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